NPY Y5 receptor antagonists

ABSTRACT

Compounds of general structural formula I such as that shown in structural formula II                    
     are selective NPY Y5 receptor antagonists, useful in the treatment of obesity and the complications associated therewith.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 09/656,698, filed Sep. 7,2000, now U.S. Pat. No. 6,313,298 which was a divisional applicationSer. No. 09/436,120, filed Nov. 8, 1999 now U.S. Pat. No. 6,191,160,which claims the benefit of provisional application Ser. No. 60/107,835,filed Nov. 10, 1998.

SUMMARY OF THE INVENTION

This invention is concerned with compounds which are spiro-indolines ofgeneral structure:

The invention is also concerned with the use of these novel compounds toselectively antagonize the Y5 receptors and thereby inhibit obsessivefood intake and the resulting obesity and complications associatedtherewith.

The invention is also concerned with pharmaceutical formulationscomprising one of the compounds as active ingredient.

The invention is further concerned with processes for preparing thecompounds of this invention.

BACKGROUND OF THE INVENTION

Neuropeptide Y (NPY) is a member of the pancreatic polypeptide familywith widespread distribution throughout the mammalian nervous system.NPY and its relatives elicit a broad range of physiological effectsthrough activation of at least six G protein-coupled receptor subtypesknown as Y1, Y2, Y3, Y4, Y5 and Y6. The Y5 subtype was isolated,characterized and reported recently in U.S. Pat. No. 5,602,024 (WO96/16542).

The cited WO 96/16542 also reports the discovery of chemical compoundswhich bind selectively to the Y5 receptor and which act as antagonistsof the Y5 receptor, several of which were shown to inhibit food intakein rats.

Now with the present invention there is provided a class of compoundscharacterized as spiro-indolines, which are useful in the treatment,control or prevention of diseases, disorders or conditions mediated byactivation of the Y5 receptor. These compounds are, thus, useful in thetreatment of obesity in man or animals and in conditions caused by orexacerbated by obesity.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the compound ofstructural formula I:

or a pharmaceutically acceptable salt thereof, wherein;

V, W, X and Z are independently selected from CH and N;

R¹ is H, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, or Cl;

R² is S(O)_(n)R⁶, COR⁶ or CHO, wherein

n is 0, 1 or2; and

R⁶ is N(R³)₂ or C₁₋₃ alkyl;

R³ is independently H or C₁₋₃ alkyl;

Ar is aryl or heteroaryl;

R⁴ and R⁵ are independently selected from:

(1) hydrogen,

(2) aryl, either unsubstituted or substituted with

(a) halo

(b) C₁₋₃ alkoxy,

(c) —N(C₁₋₃ alkyl)₂,

(d) C₂₋₄ alkanoyl, or

(e) aryl,

(3) nitro,

(4) C₁₋₅ alkyl,

(5) C₁₋₅ alkoxy,

(6) hydroxy-C₁₋₃ alkyl,

(7) carboxy,

(8) halo,

(9) C₁₋₅ alkylthio,

(10) C₁₋₅ alkoxycarbonyl,

(11) pyridylcarbonyl,

(12) benzoyl,

(13) phenyl-C₁₋₃ alkoxy,

(14) pyridyl, either unsubstituted or substituted with C₁₋₃ alkyl orC₁₋₃ alkoxy,

(15) C₃₋₆ cycloalkyl,

(16) oxazolyl,

(17) thiazolyl,

(18) triazolyl,

(19) phenoxy or

(20) C₂₋₆ alkanoyl.

The term “alkyl” means linear and branched structures and combinationsthereof, containing the indicated number of carbon atoms. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- andt-butyl, pentyl, hexyl and the like.

“Cycloalkyl” means a hydrocarbon having the indicated number of carbonatoms, containing one or more rings. Examples of cycloalkyl groups arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Halogen” or “halo” includes F, Cl, Br, and I unless otherwisespecified.

“Heteroaryl” is a 5- or 6-membered aromatic heterocycle, or a benzo- orpyrido-fused version thereof, all having, besides carbon atoms, 1 to 3hetero atoms selected from N, O, and S as atom(s) constituting the ring.Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,benzothienyl, benzofuranyl, indolyl, pyrimidinyl, pyrazinyl,pyridazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl,benzimidazolyl, pyridothiazolyl, quinolyl, isoquinolyl or triazolyl.

“Aryl” is phenyl or naphthyl.

“Alkoxy” means linear and branched structures and combinations thereof,containing the indictaed number of carbon atoms. Examples of alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s- andt-butoxy, pentoxy, and the like.

“Alkanoyl” means linear and branched structures and combinationsthereof, containing the indicated number of carbon atoms. Examples ofalkanoyl groups include, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl and the like.

One embodiment of the novel compounds of this invention is that whereinAr is phenyl of structural formula I(a)

or a pharmaceutically acceptable salt thereof.

A class of compounds within this embodiment is that wherein X and Z areboth nitrogen, and V and W are both —CH═.

A sub-class is that wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂NH₂.

A sub-sub-class of the compounds of this embodiment is that wherein R⁴and R⁵ are independently selected from: phenyl, pyridyl, benzoyl,halophenyl, phenoxy, C₁₋₅ alkylpyridyl, benzhydryl, phenyl-C₁₋₃ alkoxy,NO₂, C₂₋₄ alkanoyl, halo, C₁₋₅ alkoxy, C₁₋₃ alkoxycarbonyl, C₁₋₅alkylthio, triazolyl, carboxy, hydrogen, C₁₋₅ alkyl, pyridylcarbonyl,and C₁₋₃ alkoxyphenyl.

Typical of the compounds of this sub-sub-class are those wherein R² andphenyl(R⁴)(R⁵) are as shown in the following TABLE I:

TABLE I

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂C₂H₅

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂C₂H₅

—SO₂CH(CH₃)₂

—SO₂CH(CH₃)₂

A second embodiment of the compounds of this invention is that whereinAr is a 5- or 6-membered heteroaryl having, besides carbon atoms, 1 to 3hetero atoms selected from N, O and S as atoms constituting the ring, orbenzo- or pyrido-fused versions thereof, of structural formula I(b);

or a pharmaceutically acceptable salt thereof.

A class of compounds within this embodiment, is that wherein X and Z areboth nitrogen, and V and W are both —CH═.

A sub-class is that wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂N(C₁₋₃alkyl)₂.

A sub-sub-class of compounds within this embodiment is that wherein theheteroaryl group, Ar, is selected from: thiazolyl, thiadiazolyl,pyrazolyl, pyridyl, benzothiazolyl, oxazolyl, pyridothiazolyl,benzoxazolyl, quinolyl, pyrazinyl, thienyl, isoxazolyl, pyrimidinyl,benzimidazolyl, oxadiazolyl and imidazolyl.

Typical of the compounds of this sub-sub-class are those wherein R² andAr(R⁴)(R⁵) are as shown in TABLE II.

TABLE II

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂N(CH₃)₂

—SO₂NH₂

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅

—SO₂CH₃

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅

A third embodiment of the compounds of this invention is that whereinone of X and Z is N and the other is —CH═ of structural formula 1(c):

or a pharmaceutically acceptable salt thereof.

A class of compounds within this embodiment is that wherein X is N, Z is—CH═ and V and W are both —CH═

Typical of the compounds within this class are those shown in TABLE III:

TABLE III

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

A second class of compounds within this embodiment is that wherein X is—CH═, Z is N and V and W are both —CH═.

Typical of the compounds within this second class are those shown inTABLE IV:

TABLE IV

R² X

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

A fourth embodiment of the compounds of this invention is that whereinR² is —COR⁶ of structural formula I(d):

or a pharmaceutically acceptable salt thereof.

A class of compounds within this embodiment is that wherein X and Z areboth N and V and W are both —CH═.

Typical of the compounds within this embodiment are those shown in TABLEV:

TABLE V

R⁶

—CH₃

—CH₃

—CH₃

A fifth embodiment of the compounds of this invention is that whereinone of V or W is nitrogen (N) and the other is —CH═ of formula I(e):

A class of compounds within this embodiment is that wherein R¹ and R³are H and X and Z are both nitrogen.

A sub-class of compounds within this class is that wherein R² is—SO₂CH₃.

Typical of the compounds within this sub-class are those depicted in thefollowing TABLE VI:

TABLE VI

V W

—N═ —CH═

—CH═ —N═

—CH═ —N═

—CH═ —N═

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to include such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic and organic acids and bases.

When the compound of the present invention is acidic, salts may beprepared from inorganic bases such as aluminum, ammonium, calcium,copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc,and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine,glucosamine, histidine, hydrabamine, N-(2-hydroxyethyl)piperidine,N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, adipic,aspartic, 1,5-naphthalenedisulfonic, benzenesulfonic, benzoic,camphorsulfonic, citric, 1,2-ethanedisulfonic, ethanesulfonic,ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic,hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic,succinic, sulfuric, tartaric, p-toluenesulfonic acid, undecanoic,10-undecenoic, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuricand tartaric acids. It will be understood that in the materials whichfollows, references to the compounds of Formula I are meant to alsoinclude the pharmaceutically acceptable salts.

Another aspect of this invention are the processes used to prepare thenovel compounds.

Compounds in which X and Z are both nitrogen are prepared by the generalprocedures outlined in Scheme I.

The Cbz spiroindoline 3 is prepared according to the method described inTetrahedron 53, 10983-10992 (1997).. In one procedure 3 is treated witha reagent R²Cl, wherein R² is as defined above, in the presence of abase such as a tertiary amine, including triethylamine (Et₃N),diisopropylethylamine (DIEA), or pyridine, followed by removal of thecarbobenzyloxy (Cbz) protecting group by hydrogenolysis with hydrogenover a noble metal catalyst at room temperature and pressure in a loweralcohol such as methanol or ethanol, or an etherial solvent such asdiethyl ether of tetrahydrofuran (THF) or mixtures thereof to give 4following the methods described in Tetrahedron 53 10983-10992, (1997)wherein the preparation of 4 is described wherein R² is —SO₂CH₃.

Compound 4 (with R² protected if necessary) is then treated with aphenyl carbamate of structure PHOCONH—Ar(R⁴)(R⁵) in the presence of atertiary amine in an organic solvent such as a haloalkane such aschloroform, methylene chloride, ethylene dichloride or the like atreflux temperature or in the presence of NaOH in H₂O/DMSO, until thereaction is complete, usually in about ½ to about 3 hours followed bydeprotection of the R² group if necessary, to provide the CompoundI(R³═H).

In the above procedures, the phenyl carbamates are prepared by reactionof the corresponding amines of structure NH₂—Ar(R⁴)(R⁵) which arecommercially available or readily synthesized, with phenyl chloroformatein pyridine at room temperature as described in Example I below.

Alternatively, Compound I is prepared by treatment of 4 with anisocyanate of structure OCN—Ar(R⁴)(R⁵) in a chlorinated alkane at refluxtemperature until the reaction is complete in about 4 to about 12 hours.

Compound I can also be prepared by conducting the above procedures inthe reverse order. The indoline nitrogen of 3 is protected with Boc bytreatment with di-tert-butyl dicarbonate in the presence of a base, suchas, NaOH or triethyl amine, in an inert solvent such as aqueous dioxaneor methanol and the Cbz group is hydrogenolyzed with hydrogen and anoble metal catalyst to give 5. Treatment of 5 with either the phenylcarbamate or isocyanate described earlier provides 6 which upondeprotecting with a strong acid such as hydrochloric or trifluoroaceticacid in an inert solvent such as ethyl acetate or methylene chloride andtreatment with R²Cl in the presence of a tertiary amine as describedabove provides Compound I( R³═H).

Compounds of this invention are antagonists of the Y5 receptor and assuch are useful for the prevention and treatment of disorders ordiseases associated with the Y5 receptor sub-type, preferably for thetreatment of feeding disorders such as obesity, anorexia nervosa andbullimia nervosa, and other abnormal conditions, such as diabetes,hypertension, hyperlipemia, hypercholesterolemia, congestive heartfailure, renal dysfunction, sexual/reproductive disorders, depression,anxiety, shock, epileptic seizure, memory loss, sleep disturbance, pain,migraine, cerebral hemorrhage, nasal congestion, gastrointestinaldisorders, arthritis and immunodeficiency syndrome.

The Y5 antagonists of this invention may also be used in combinationwith other anti-obesity agents for increased efficacy in the preventionand treatment of obesity Such agents would include, but not be limitedto: sibutramine; dexenfluramine; leptin; growth hormone secretagoguessuch as those disclosed and specifically described in U.S. Pat. No.5,536,716; melanocortin agonists such as Melanotan II; Beta-3 agonistssuch as those disclosed and specifically described in patentpublications WO94/18161, WO95/29159, WO97/46556, WO98/04526 andWO98/32753; 5HT-2 agonists; orexin antagonists; melanin concentratinghormone antagonists; galanin antagonists; CCK agonists; GLP-1 agonists;corticotropin-releasing hormone agonists; and Y1 antagonists.

The method of treatment of this invention comprises a method ofantagonizing the Y5 receptor and treating Y5 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the Y5 receptor in preference to the other NPYreceptors.

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg ofbody weight per day are useful in the treatment of the above-indicatedconditions, or alternatively about 0.5 mg to about 7 g per patient perday. For example, obesity may be effectively prevented or treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day, or alternatively about 0.5 mg to about 3.5 g perpatient per day.

For the treatment of any of these Y5 receptor mediated diseases,compounds of the invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

The novel pharmaceutical compositions of this invention containing theactive ingredient may be in a form suitable for oral use, for example,as tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Compounds of the invention may also be administered in the form of asuppository for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable nonirritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The following Examples describe the laboratory synthesis of specificcompounds of the invention and are not meant to limit the scope of theinvention in any way with respect to compounds or processes. It isunderstood that, although specific reagents, solvents, temperatures andtime periods are used, there are many possible equivalent alternativesthat can be used to produce similar results. This invention is meant toinclude such equivalents.

Abbreviations used herein have the following meanings:

ABBREVIATION DEFINITION Ac acetyl Boc t-butoxycarbony BSA bovine serumalbumin MCPBA m-chloroperbenzoic acid Cbz carbobenzyloxy Et ethyl HEPES[4-(2-hydroxyethyl)-1- piperazineethane sulfonic acid] IPE isopropylether Me methyl PCC pyridium chlorochromate PhMe—MeCN tolueneacetonitrile PMSF -toluene sulfonylfluoride WSC.HCl water solublecarboiimide.HCl

EXAMPLE 1 1-Methanesulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide100

Step 1: Preparation of Compound 1-2

Phenyl chloroformate (0.64 mL, 5.1 mmol) was added to a vigorouslystirred solution of 2-amino-5-phenylpyrazine 1-1 (794 mg, 4.64 mmol) inpyridine (10 mL) at room temperature. After being stirred at roomtemperature overnight, the mixture was diluted with EtOAc to give asuspension, in which the desired compound precipitated out. Thesuspension was successively washed with 1 N KHSO₄, brine and dist.water. The precipitate was collected by filtration and dried to givephenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (847 mg, 63%). The filtratewas concentrated under reduced pressure to produce precipitate, whichwas collected and dried to give the second crop (340 mg, 25%).

Step 2: Preparation of Compound 100

A mixture of phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (7, 350 mg,1.20 mmol), 1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride1-3 (400 mg, 1.32 mmol) and Et3N (0.5 mL, 3.6 mmol) in CHCl3 (6 mL) washeated to reflux for 3 h. After cooling, the mixture was diluted withEtOAc, washed with 10% citric acid, sat. NaHCO₃ and brine, dried overMgSO₄, and concentrated under reduced pressure to start precipitation.The precipitate was collected by filtration and dried in vacuo to give100 (517 mg, 93%) as a white powder.

m.p.: 201-203° C.

¹H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS: 464 (M+H)

Compounds #101-#137 were prepared from1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride and theappropriate phenyl carbamates according to the procedure described inExample 1.

#101

N-[5-(3-fluorophenyl)-2-pyrazinyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 203-205° C.

#102

N-[5-(2-methoxyphenyl)-2-pyrazinyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 186-188° C.

#103

N-[5 -(2-chlorophenyl)-2-pyrazinyl]- 1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 197-199° C.

#104

1-methylsulfonyl-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 234-235° C.

#105

1-methylsulfonyl-N-[5-(2-propenyl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 180.5-182.7° C.

#106

1-methylsulfonyl-N-[4-(1-mehtyl-2-imidazolyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

m.p.: 196-198° C.

#107

N-[4-(2-ethyl-4-thiazolyl)phenyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 242-242.5° C.

#108

1-methylsulfonyl-N-[4-(4-pyridyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 272-274° C.

#109

N-[4-(2-ethyl-4-pyridyl)phenyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

m.p.: 220-222° C.

#110

N-(4-benzoylphenyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

m.p.: 222-225° C.

#111

1-methylsulfonyl-N-[4-(2-thiazolyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 143.2-147.4° C.

#112

1-methylsulfonyl-N-(5-phenyl-2-pyridyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 214° C.

#113

1-methylsulfonyl-N-(2-phenyl-5-pyrimidinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 251-253° C.

#114

1-methylsulfonyl-N-(2-phenyl-5-pyridyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 224° C.

#115

1-methylsulfonyl-N-(5-phenyl-2-pyrimidinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 122-123° C.

#116

1-methylsulfonyl-N-[2-(1-pyrrolidinyl)-5-pyridyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 252-254° C.

#117

N-[5-(4-chlorophenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 152-156° C.

#118

N-[5-(5-methoxy-3-pyridyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 213-215° C.

#119

1-methylsulfonyl-N-(4-phenyloxazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 189-192° C.

#120

N-[5-(3-methoxyphenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 158-160° C.

#121

1-methylsulfonyl-N-(3-phenylisoxazol-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 235-237° C.

#122

N-[5-(3-chlorophenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 185-187° C.

#123

1-methylsulfonyl-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 133-136° C.

#124

N-[4-(3-methoxyphenyl)oxazol-2-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidecolorless amorphous solid.

1H-NMR (DMSO-d6) ppm: 1.62-1.87 (4H, m), 2.96-3.09 (2 H, m), 3.05 (3H,s), 3.78 (3H, s), 3.92 (2H, s), 4.04-4.16 (2H, m), 6.87 (1H, m), 7.04(1H, m), 7.19-7.37 (7H, m), 8.35 (1H, br s).

#125

1-methylsulfonyl-N-(5-phenylpyrrazol-3-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 163° C.

#126

N-[1-(3-methoxyphenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 216-218° C.

#127

N-[1-(3-chlorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 232-234° C.

#128

N-(4-methoxybenzoxazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 195-199° C.

#129

N-(5-fluorobenzothiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 243-244° C.

#130

1-methylsulfonyl-N-(6-methylquinoxalin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 224-225° C.

#131

1-methylsulfonyl-N-(8-methylquinolin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 219-220° C.

#132

N-(7-chloroquinoxalin-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 213-214° C.

#133

N-(6-methoxypyrido[2,2-d]thiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 179-182° C.

#134

N-(5-methoxybenzoxazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 194-196° C.

#135

N-(5-chlorobenzoazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 172-176° C.

#136

1-methylsulfonyl-N-(1,5-naphthyridin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

1H-NMR (DMSO-d6) ppm: 1.64-1.92 (4H, m), 2.95-3.16 (2H, m), 3.05 (3H,s), 3.93 (2H, s), 4.18-4.30 (2H, m), 7.04 (1H, m), 7.18-7.37 (3H, m),7.66 (1H, dd, J=4.3, 8.5 Hz), 8.14 (1H, m), 8.22-8.30 (2H, m), 8.80 (1H,m), 9.84 (1H, br s).

#137

N-(4-methylbenzothiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 182-183° C.

Compound #138 was prepared from7-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 1.

#138

7-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

1H-NMR (CDCl3) δ ppm: 1.62-1.96 (4H, m), 3.09-3.18 (2H, m), 3.33 (3H,s), 4.14-4.26 (2H, m), 6.93-7.10 (3H, m), 7.90 (1H, brs), 7.97 (2H, d,J=6.8 Hz), 8.56 (1H, s), 9.54 (1H, d, J=2.3 Hz).

Compound #139 was prepared from6-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 1.

#139

6-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 234-237° C.

Compounds #140-144 were prepared from1-ethylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [prepared inanalogy to the method described in U.S. Pat. No. 5,536,716] and thecorresponding phenyl carbamates according to the procedure described inExample 1.

#140

1-ethylsulfonyl-N-(1-phenylimidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

m.p.: 139-140° C.

#141

N-(4-benzoylphenyl)-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

1H-NMR (CDCl3) δ ppm: 1.44 (3H, t, J=7.4 Hz), 1.80-1.85 (2H, m),1.95-2.04 (2H, m), 3.10-3.20 (2H, m), 3.17 (2H, t, J=7.4 Hz), 3.97 (2H,s), 4.11-4.16 (2H, m), 6.8-6.9 (1H, brs), 7.08 (1H, t, J=7.3 Hz), 7.16(1H, d, J=8.1 Hz), 7.23 (1H, d, J 8.1 Hz), 7.37 (1H, d, J=8.1 Hz),7.48-7.58 (5H, m), 7.76-7.83 (4H, m).

#142

N-[5-(4-chlorophenyl)pyrrazol-3-yl]-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 249.0-249.8° C.

#143

N-[5-(4-chlorophenyl)isoxazol-3-yl]-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 178.3-178.5° C.

#144

1-ethylsulfonyl-N-[1-(3-methoxyphenyl)imidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid

1H NMR (CDCl3) δ ppm: 1.43 (3H, t, J=7.5 Hz), 1.75-1.82 (2H, m),1.89-2.00 (2H, m), 3.01-3.13 (2H, m), 3.16 (2H, q, J=7.5 Hz), 3.85 (3H,s), 3.96 (2H, s), 4.10-4.20 (2H, m), 6.86-6.90 (1H, m), 6.93-6.95 (1H,m), 6.98-7.07 (2H, m), 7.14 (1H, d, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz),7.33-7.41 (3H, m), 7.56 (1H, s), 7.60 (1H, s).

Compound #145 was prepared from1-ethylsulfonyl-5-fluorospiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(1-phenylimidazol-4-yl)carbamate according to the proceduredescribed in Example 1.

#145

1-ethylsulfonyl-5-fluoro-N-(1-phenylimidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

m.p.: 140-141° C.

#146

1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 247-249° C.

#147

1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 234-238° C.

#148

6-fluoro-1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 242-243° C.

#149

6-fluoro-1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 237-239° C.

Compounds #150 and #151 were prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and the corresponding phenyl carbamates according to the proceduredescribed in Example 1.

#150

5-fluoro-1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 262-266° C.

#151

5-fluoro-1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 239-240° C.

#152

1-ethylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 193-194° C.

#153

1-ethylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 211-214° C.

Compound #154 was prepared from1-ethylsulfonyl-6-fluorospiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]carbamate accordingto the procedure described in Example 1.

#154

1-ethylsulfonyl-6-fluoro-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 228-230° C.

#155

1-ethylsulfonyl-5-fluoro-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

m.p.: 223-224° C.

EXAMPLE 2N-(2-benzothiazolyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide200

10 M aqueous NaOH solution (75 uL) was added to a solution of1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 2-1 (225mg, 0.74 mmol) in DMSO (2.5 mL). Phenyl N-(2-benzothiazolyl)carbamate2-2 (200 mg, 0.74 mmol) was added to the mixture, and the resultingmixture was stirred at room temperature for 20 h. The mixtrue wasdiluted with water and extracted with EtOAc. The organic extract waswashed with dil. NaOH and brine, and dried over Na₂SO₄. The solvent wasevaporated, and the residue was purified by silica gel columnchromatography to give 200 (279 mg, 85%) as a colorless amorphous solid.

1H-NMR (CDCl3) δ ppm: 1.72-1.84 (2H, m), 1.88-2.00 (2H, m), 2.92 (3H,s), 3.06 (2H, t, J=13.0 Hz), 3.86 (2H, s), 4.23-4.33 (2H, m), 7.03-7.16(2H, m), 7.20-7.28 (3H, m), 7.38-7.42 (2H, m), 7.51-7.61 ( H, m),7.70-7.75 (1H, m). FABMS: 443 (M+H)

Compound #201 was prepared from1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [preparedby the method described in U.S. Pat. No. 5,536,716] and phenylN-(3-biphenylyl)carbamate according to the procedure described inExample 2.

#201

N-3-biphenyl-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide m.p.: 211-212° C.

Compound #202 was prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 2.

#202

5-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 215.5-215.8° C.

Compound #203 and #204 were prepared from1-ethylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [prepared inanalogy to the method described in U.S. Pat. No. 5,536,716] and phenylN-[1-(3-fluorophenyl)-4-imidazolyl]carbamate or phenylN-[1-(2-fluorophenyl)-4-imidazolyl]carbamate, respectively, according tothe procedure described in Example 2.

#203

1-ethylsulfonyl-N-[1-(3-fluorophenyl)imidazol-4-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 200-202° C.

#204

1-ethylsulfonyl-N-[1-(2-fluorophenyl)imidazol-4-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 180-181.5° C.

EXAMPLE 3N-(4-acetylphenyl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide300

1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 was preparedby the procedure described in WO 9602530.

To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate3-2 (92 mg, 0.36 mmol) in CHCL₃ (3 mL) was added Et₃N (0.23 mL, 1.65mmol) at room temperature. The reaction mixture was heated to reflux for1 h. The resulting suspension was cooled to room temperature. Theresulting suspension was filtered and the filter cake was washed withCHCl₃ to give 300 (47 mg, 33%) as a white solid. m.p.: 233-236° C.

1H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS:429 (M+H)

EXAMPLE 4N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide400

Step 1: Preparation of compound 4-2

Chlorosulfonyl isocyanate (2.70 mL, 31.1 mmol) was added to a stirredsolution of tert-butyl alchol (2.96 mL, 31.1 mmol) in EtOAc (400 mL) at−40° C., and the resulting mixture was stirred at −20° C. for 20 min.The mixture was cooled to −78° C., and a solution of 4-1 (5.00 g, 15.5mmol) in EtOAc (40 mL) was added to the reaction mixture. The mixturewas allowed to warm to room temperature and stirred for 14 h. Thereaction mixture was washed with sat.NaHCO₃, H₂O and brine, dried(Na₂SO₄), and concentrated. The residual oil was purified by silica gelcolumn chromatography (80 g, hexane-EtOAc 4:13:12:1) to give 4-2 (2.13g, 27%).

Step 2: Preparation of compound 4-3

A mixture of compound 4-2 (411 mg, 0.820 mol) and 20% Pd(OH)₂-C (200 mg)in THF (4 mL) and MeOH (4 mL) was stirred under atmospheric pressure ofhydrogen for 3 h. The catalyst was filtered off, and the filtrate wasconcentrated to give compound 4-3 (215 mg, 71%).

Step 3: Preparation of compound 4—4

Et₃N (0.285 mL, 1.46 mmol) was added to a stirred mixture of 4-3 (250mg, 0.681 mmol) and phenyl 5-phenyl-1,3,4-thiadiazol-2-ylcarbamate (202mg, 0.681 mmol) in CHCl₃ (3 mL), and the mixture was heated to refluxfor 3 h. After being cooled to room temperature, the mixture wasconcentrated under reduced pressure. The residual oil was purified bysilica gel column chromatography (10 g, hexane-EtOAc-MeOH 1:1:0→8:8:1)to give 4—4 (208 mg, 54%).

Step 4 Preparation ofN-(5-phenyl-1,3,4-thiadiazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide400

To a stirred mixture of 4—4 in CHCl₃ (1 mL) was added TFA (1 mL). Themixture was stirred for 14 h and concentrated. The resulting mixture wasdiluted with EtOAc, washed with sat.NaHCO₃ and brine, dried (Na₂SO₄),and concentrated. The residual solid was crystallized from EtOAc andisopropyl ether to give compound 400 (130 mg, 76%) as colorlesscrystals. m.p.:>300° C.

1H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS: 471 (M+H)

Compounds #401 and #402 were prepared using the appropriate phenylcarbamates in analogy to the procedure of Example 4.

#401

N-(4-phenyloxazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamidecolorless amorphous solid.

1H-NMR (DMSO-d6) δ ppm: 1.59-1.69 (2H, m), 1.71-1.85 (2H, m), 2.95-3.10(2H, m), 3.81 (2H, s), 4.05-4.17 (2H, m), 6.98 (1H, m), 7.17 (1H, m),7.18-7.48 (6H, m), 7.68-7.75 (2H, m), 8.33 (1H, s).

#402

N-(3-phenylisoxazol-5-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 226-227° C.

EXAMPLE 51-Methanesulfamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide500

Step 1: Preparation of compound 5-2

To a stirred solution of 5-1 (542 mg, 1.08 mmol) and iodomethane (0.202mL, 3.24 mmol) in DMF (3 mL) was added sodium hydride (contained 60% oildispersion, 52 mg; 1.30 mmol) at 0° C. The mixture was stirred at roomtemperature for 2 h. The reaction mixture was poured into sat. NH₄Cl andextracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), and concentrated. The residual oil was purified by silica gelcolumn chromatography (20 g, hexane-EtOAc 6:1→4:1) to give compound 5-2(495 mg, 83%).

Step 2: Preparation of compound 5-3

A mixture of 450 mg (0.898 mmol) of 5-2 and 200 mg of 20% Pd(OH)₂-C inTHF (5 mL) and MeOH (5 mL) was stirred under H₂ for 14 h. The catalystwas then filtered off and the filtrate was concentrated to give compound5-3 (371 mg, 99%).

Step 3: Preparation of1-methylsulfamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide500

To a stirred mixture of 5-3 (185 mg; 0.486 mmol)and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate (144 mg; 0.486 mmol) in CHCl₃ (2mL) was added 0.285 mL (1.46 mmol) of Et₃N. The mixture was refluxed for3 h and cooled to room temperature. Isopropyl ether was added to themixture, and the resulting precipitate was collected by filtration togive crude product of 5-4.

The crude product was dissolved in CHCl₃ (1 mL), and TFA (1 mL) wasadded. The mixture was stirred for 14 h and concentrated. The residuewas dissolved in EtOAc, washed with sat.NaHCO₃ and brine, dried(Na₂SO₄), and concentrated. The residue was triturated with CHCl₃ togive 500 (130 mg, 55%) as a colorless solid. m.p.: 230-231° C.

1H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS: 485 (M+H)

EXAMPLE 61-Acetyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide600

Step 1: Preparation of Compound 6-2

To a solution of 6-1 (267 mg, 0.87 mmol) in THF (5 mL), were added Et₃N(0.356 mL, 2.56 mmol) and AcCl (0.092 mL, 1.30 mmol). The resultingmixture was stirred at room temperature for 1 h. The mixture was dilutedwith ethyl acetate, washed with saturated NaHCO₃ and brine, dried(MgSO₄), and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane/ethyl acetate2/1→1/1→1/2→1/4→1/8 (v/v)) to give 6-2 (260 mg, 82%).

Step 2 Preparation of Compound 6-3

To a solution of 6-2 (260 mg, 0.71 mmol) in EtOH/THF (6 mL/2 mL), wasadded 20% Pd(OH)₂-C (110 mg). The resulting mixture was stirred under H₂at room temperature overnight. The catalyst was filtered off, and thefiltrate was concentrated under reduced pressure to give 6-3 (155 mg,91%).

Step 3: Preparation of Compound 600

To a solution of 6-3 (155 mg, 0.67 mmol) in CHCl₃ (3 mL), were addedEt₃N (0.256 mL, 1.84 mmol) and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate 6-4 (182 mg, 0.61 mmol). Theresulting mixture was stirred under reflux for 1.5 h. After being cooledto room temperature, the reaction mixture was diluted with CHCl₃, washedwith saturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. The residue was triturated withEt₂O to give 600 (176 mg, 66%) as a white solid. m.p.: 260° C.

1H-NMR (CDCl3) was consistent with the proposed title structure. FABMS:434 (M+H).

Employing the procedure substantially as described in Example 6, butsubstituting the appropriate phenyl carbamates, for the phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate used in Step 3 thereof, thefollowing compounds were prepared:

#601

1-acetyl-N-(4-biphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#602

1-acetyl-N-(4-phenyloxazol-2-yl)spiro[indoline-3.4′-piperidine]-1′-carboxamide

#603

1-acetyl-N-[3-(3-chlorophenyl)isoxazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

#604

1-acetyl-N-[4-(3-pyridyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

#605

1-acetyl-N-[3-(4-chlorophenyl)pyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

#606

1-acetyl-N-(7-methoxybenzothiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#607

1-acetyl-N-(2-methylbenzothiazol-6-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#608

1-acetyl-N-(quinolin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#609

1-acetyl-N-[3-(3-methoxyphenyl)-1-methylpyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

#610

1-acetyl-N-[3-(3-chlorophenyl)-1-methylpyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

#611

1-acetyl-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[indoline-3,4′piperidine]-1′-carboxamide

#612

1-acetyl-N-(3-phenylpyrazol-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#613

1-acetyl-N-(2-phenylpyrazin-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#614

1-acetyl-N-(3-phenylpyridazin-6-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#615

1-acetyl-N-(5-phenylpyrimidin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

#616

1-acetyl-N-(2-phenylpyrimidin-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

EXAMPLE 71-Formyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide700

Step 1: Preparation of Compound 7-2

A mixture of 7-1 (300 mg, 3.54 mmol) and p-TsOH.H₂O (10 mg) in ethylformate (5 mL) was stirred under reflux for 20 hr. After being cooled toroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was taken up with CHCl₃, which was washed withsaturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane/ethyl acetate 4/1→1/1 (v/v)) to give7-2 (290 mg, 89%).

Step 2: Preparation of Compound 7-3

To a solution of 7-2 (290 mg, 0.83 mmol) in EtOH/THF (7 mL/5 mL) wasadded 20% Pd(OH)₂-C (360 mg). The resulting mixture was stirred under H₂at room temperature overnight. The catalyst was filtrated off, and thefiltrate was concentrated under reduced pressure to give 7-3 (160 mg,89%).

Step 3: Preparation of Compound 700

Compound 7-3 (320 mg, 1.48 mmol) was dissolved in CHCl₃ (5 mL), and Et₃N(0.560 mL, 4.02 mmol) and phenyl 5-phenyl-1,3,4-thiadiazol-2-ylcarbamate(400 mg, 1.34 mmol) were added. The resulting mixture was stirred underreflux for 1 h. The reaction mixture was cooled to room temperature anddiluted with CHCl₃, which was washed with saturated NaHCO₃ and brine.The organic layer was dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane/ethyl acetate/methanol 10/1/0→6/1/0→1/1/0→6/6/1→3/3/1→1/1/1(v/v/v)) to give 7-4 (200 mg, 72%) as a white amorphous solid.

1H-NMR (CDCl3) was consistent with the proposed title structure. FABMS:420 (M+H)

EXAMPLE 81-Dimethylcarbamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide800

Step 1: Preparation of Compound 8-2

To a solution of 8-1 (400 mg, 1.30 mmol) in DMF (3 mL), was added NaH(62 mg, 2.60 mmol, washed with dry n-hexane before use), and the mixturewas stirred at room temperature for 30 min. Dimethyl carbamoyl chloride(0.18 mL, 1.95 mmol) was added to the mixture, and the reaction mixturewas stirred at room temperature for 24 h. The mixture was diluted withethyl acetate, washed with saturated NaHCO₃ and brine, dried (MgSO₄),and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (n-hexane/ethyl acetate 1/1→1/2→1/4(v/v)) to give 8-2 (535 mg) as a crude product.

Step 2 Preparation of Compound 8-3

To a solution of 8-2 (535 mg, 1.36 mmol) in EtOH/THF (3 mL/1 mL) wasadded 20% Pd(OH)₂-C (200 mg). The resulting mixture was stirred under H₂at room temperature overnight. The catalyst was filtrated off, and thefiltrate was concentrated under reduced pressure to give 8-3 (320 mg,95%, two steps).

Step 3: Preparation of Compound 800

Compound 8-3 (300 mg, 1.16 mmol) was dissolved in CHCl₃ (3 mL), and Et₃N(0.44 ml, 3.15 mmol) and phenyl 5-phenyl-1,3,4-thiadiazol-2-ylcarbamate(317 mg, 1.05 mmol) were added. The resulting mixture was stirred underreflux overnight. The reaction mixture was cooled to room temperatureand extracted with CHCl₃, which was washed with a saturated NaHCO₃ andbrine. The organic layer was dried (MgSO₄) and concentrated underreduced pressure. The residue was triturated with Et₂O to give 800 (334mg, 69%) as a white solid. m.p.: 267° C.

1H-NMR (CDCl3) was consistent with the proposed title structure. FABMS:463 (M+H)

Compounds, in which X is carbon atom and Z is nitrogen atom in thefollowing general formula, are generally prepared according to Example9.

EXAMPLE 91-Acetyl-N-(3-guinolinyl)spiro[indoline-3,4′-cyclohexane]-1′-carboxamide900

Step 1: Preparation of Compound 9-1

A mixture of terephthalic acid monomethylester (40.0 g, 0.222 mol) and5% Rh-C (wet) (40 g) in 1,4-dioxane (200 mL) and MeOH (160 mL) wasstirred under H₂ at 50 atm for 18 h. The catalyst was then filtered offand the filtrate was concentrated to give 41.0 g (99%) of 9-1.

Step 2: Preparation of Compound 9-2

To a stirred solution of 41.0 g (0.220 mol) of 9-1 in THF (200 mL)cooled at 0° C. was added 27.4 mL (0.289 mol) of Me₂S.BH₃. The solutionwas stirred at room temperature for 3 h and AcOH (6 mL) was added. Theresulting mixture was diluted with H₂O and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated togive 36.1 g (95%) of 9-2.

Step 3: Preparation of Compound 9-3

To a stirred mixture of Celite (10 g) and 9-2 (3.00 g; 17.4 mmol) inCH₂Cl₂ (60 mL) was added PCC (11.3 g; 52.3 mmol). The mixture wasstirred at room temperature for 3 h and diluted with hexane (100 mL).The resulting mixture was then filtered and the filtrate wasconcentrated to give 9-3 (2.65 g; 90%).

Step 4: Preparation of Compound 9-4

To a stirred solution of 9-3 (2.65 g; 15.6 mmol) in 35 mL of PhMe-MeCN(39:1) cooled at 0° C. were added phenylhydrazine (1.54 mL; 15.6 mmol)and TFA (3.61 mL; 46.8 mmol). The mixture was stirred at roomtemperature for 16 h and MeOH (35 mL) was added. The mixture was cooledto 0° C. and NaBH₄ (885 mg; 23.4 mmol) was added and stirred at 0° C.for 1 h. The reaction mixture was poured into sat. NaHCO₃ and extractedwith EtOAc. The organic layer was washed with H₂O and brine, dried(Na₂SO₄), and concentrated to give the crude product 9-4 (3.60 g).

Step 5: Preparation of Compound 9-5 and 9-6

To a stirred solution of crude product 9-4 in THF (50 mL) cooled at 0°C. were added Et₃N (6.52 mL; 46.8 mmol) and AcCl. (2.22 mL; 31.2 mmol)The mixture was stirred at 0° C. for 1 h then poured into 10% citricacid. The resulting mixture was extracted with EtOAc. The organic layerwas washed with sat. NaHCO₃ and brine, dried (Na₂SO₄), and concentrated.The residual oil was purified by silica gel column chromatography (100g, hexane-EtOAc 3:1→2:1→4:3) to give 577 mg of 9-5 (14%) and 1.42 g ofthe mixture of 9-5 and 9-6 (33%).

Step 6: Preparation of Compound 9-7 and 9-8

To a stirred solution of 9-6 (1.42 g; 5.20 mmol) in MeOH (20 mL) wasadded 4N NaOH (5.2 mL; 20.8 mmol). The solution was stirred at roomtemperature for 3 h and the MeOH was concentrated. 1N HCl (30 mL) wasadded and extracted with EtOAc. The organic layer was washed with brine,dried (Na₂SO₄), and concentrated. The residual oil was purified bysilica gel column chromatography (80 g, CHCl₃-MeOH 1:0 200:1 100:1) togive 367 mg of 9-7 (26%) and 627 mg of 9-8 (44%).

Step 7: Preparation of Compound 900

To a stirred solution of 20 mg (73.3 mmol) of 9-7 (20 mg; 73.3 mmol) and3-aminoquinoline (21 mg; 73.3 mmol) in pyridine (0.5 mL) was addedWSC.HC (21 mg; 101 mmol. The mixture was stirred at 50° C. for 1 h. Thereaction mixture was poured into H₂O and extracted with EtOAc. Theorganic layer was washed with H₂O and brine, dried (Na₂SO₄), andconcentrated. The residual oil was purified by silica gel columnchromatography (5 g, hexane-EtOAc-MeOH 1:1:0→8:8:1→6:6:1→4:4:1) to give900 (17.0 mg; 58%) as a colorless amorphous solid.

1H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS: 400 (M+H)

The following compounds #901-#905 were prepared from the appropriateamines in analogy to the procedure of Example 9.

#901

trans-N-(4-biphenylyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 119.8-120.5° C.

#902

trans-1-methylsulfonyl-N-[4-(3-pyridyl)phenyl]spiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 212.5-213.0° C.

#903

trans-1-methylsulfonyl-N-(5-phenylpyrrazol-3-yl)spiro[indoline-3,4-cyclohexane]-1′-carboxamidem.p.: 212-213° C.

#904

trans-N-[1-(3,5-difluorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 287-292° C.

#905

trans-N-[1-(4-fluorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 264-266° C.

EXAMPLE 102,3-Dihydro-1-methanesulfonyl-N-(5-phenyl-pyrazinyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamide1000

Step 1: Preparation of Compounds 10-2 and 10-3

Indene 10-1 was synthesized by the method described in U.S. Pat. No.5,536,716

To a solution of indene 10-1 (9.82 g, 34.4 mmol) in THF (100 mL) wasslowly added 2M BH₃.SMe₂ in THF (24.1 mL, 48.2 mmol) at 0°. After beingstirred for 4 h at 0°, the mixture was treated with 2N NaOH (100 mL) and30% H₂O₂ (25 mL) for 30 min at 0°. The organic layer was separated andthe aqueous layer was extracted with ether (100 mL×2). The combinedorganic layer was washed with 5% Na₂S₂O₃ aqueous and brine, dried(Na2SO4), and was evaporated off. The residue was purified by silica gelcolumn chromatography hexane/ethyl acetate (600 mL 4/1→2/1) to give 10-2(4.83 g, 46%) as an amorphous solid and its regioisomer 10-3 (5.02 g,48%) as a solid.

Step 2: Preparation of Compound 10-4

To a solution of alcohol 10-2 (4.83 g, 15.9 mmol) in CHCl₃ (70 mL) andtriethylamine (6.65 mL) was slowly added methanesulfonyl chloride (2.46mL) at 0°. The mixture was stirred for 15 min and was diluted with Et₂O.The organic layer was washed with aqueous NH₄Cl, saturated aqueousNaHCO₃ and brine, dried (Na₂SO₄) and concentrated in vacuo.

The residue was dissolved in DMF (40 mL) and sodium thiomethoxide (2.23g, 31.8 mmol) was added to the solution. After being stirred for 50 minat room temperature, the resulting mixture was poured into water, andextracted with Et₂O, and washed with water and brine. The organic layerwas dried (Na₂SO₄) and concentrated in vacuo.

The residue was dissolved with CHCl₃ (100 mL) and MCPBA (10.3 g, 47.7mmol) was added to the solution at 0°. After being stirred for 20 min at0°, to the suspension was added aqueous Na₂S₂O₃ and aqueous NaHCO₃. Themixture was extracted with Et₂O, and washed with saturated NaHCO₃aqueous twice and brine. The organic layer was dried (MgSO₄), andconcentrated in vacuo. The residue was purified by silica gelchromatography (Merck 7734, 300 mL, Hexane/ethyl acetate=1/1) to give5.33 g (92%) of sulfone 10-4.

Step 3: Preparation of Compound 10-5

Sulfone 10-4 (5.27 g) was dissolved in ethyl acetate (50 mL) and thesolution was treated with 4N HCl in ethyl acetate (10 mL) at 0°. Afterbeing stirred for 2.5 hr. at room temperature, to the mixture was againadded 4N HCl in ethyl acetate (10 mL). After being stirred for 2.5 h,the resulting mixture was evaporated and the residue was suspended inethyl acetate and collected to give amine HCl salt 10-5 (3.72 g; 85%) asa white solid.

Step 4: Preparation of Compound 1000

Amine HCl salt 10-5 (160 mg) and phenoxy compound 10-6 (153 mg, 0.53mmol) were suspended in CHCl₃ (3.0 mL) and triethylamine (0.16 mL), andthe suspension was refluxed for 3 h. The resulting mixture was cooled toroom temperature. After diluting with ethyl acetate, the organic layerwas washed with NH₄Cl aqueous, saturated aqueous NaHCO₃ and brine. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo. The residuewas suspended with ethyl acetate and IPE, and collected to give urea1000 (177 mg) as a solid.

The following compounds were prepared by the procedures deesdcribed inExample 10 procedure of Example 10.

#1001

2,3-dihydro-1-methylsulfonyl-N-(4-phenyl-2-oxazolyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamideamorphous solid.

1H-NMR (CDCl3) δ ppm: 1.79-1.87 (2H, m), 2.00-2.10 (2H, m), 2.42 (1H,dd, J=14.5 Hz, 6.5 Hz), 2.75 (1H, dd, J=14.5 Hz, 9.6 Hz), 2.80 (3H, s),2.99-3.09 (2H, m), 4.56-4.61 (2H, m), 4.72 (1H, dd, J=9.6Hz, 6.5 Hz),7.21 -7.49 (10H, m), 7.69 (1H, d, J 7.6 Hz).

#1002

2,3-dihydro-1-methylsulfonyl-N-[3-(3-chlorophenyl)-5-isoxazolyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamideamorphous solid.

1H-NMR ((CD3)2CO) δ ppm: 1.89-2.06 (4H, m), 2.74 (1H, dd, J=14.3 Hz, 6.2Hz), 2.79 (1H, dd, J=14.3 Hz, 9.3 Hz), 2.96 (3H, s), 3.20-3.23 (2H, m),4.30-4.35 (2H, m), 4.94 (1H, dd, J=9.3 Hz, 6.2 Hz), 6.63 (1H, s),7.29-7.34 (1H, m), 7.38-7.40 (2H, m), 7.52-7.54 (2H, m), 7.66 (1H, d,J=7.5 Hz), 7.81-7.84 (1H, m), 7.89 (1H, d, J=1.2 Hz), 9.50 (1H, s).

EXAMPLE 11

2,3-Dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-pipendine]-1-carboxamide 1100

Step 1: Preparation of Compound 11-2

To a solution of alcohol 11-1 (1.05 g, 3.46 mmol) in CHCl₃ (15 mL) andtriethylamine (1.45 mL, 10.4 mmol) was added methanesulfonyl chloride(0.535 mL, 6.92 mmol) at 0°. The mixture was stirred for 15 min and wasdiluted with Et₂O. The organic layer was washed with NH₄Cl aqueous,aqueous saturated NaHCO₃ and brine, dried (Na₂SO₄) and concentrated invacuo. The residue was dissolved in DMSO (15 mL) and potassiumthioacetate (395 mg, 31.1 mmol) was added to the solution. After beingstirred for 1.5 h at room temperature, the resulting mixture was pouredinto water and extracted with Et₂O. The organic layer was washed withwater and brine, dried (Na₂SO₄), and concentrated in vacuo. The residuewas purified by a silicagel chromatography (WAKO C-200, Hexane/ethylacetate=8/1→5/1) to give thioacetate 11-2 (1.05 g; 89%).

Step 2: Preparation of Compound 11-3

Thioacetate 11-2 (222 mg, 0.614 mmol) was dissolved in ethyl acetate(2.0 mL) and the solution was treated with 4N HCl in ethyl acetate (5.0mL). After being stirred for 3.5 h. at room temperature, the resultingmixture was evaporated and the residue was co-evaporated three timeswith CHCl₃, was diluted and collected to give amine HCl salt 11-3 (201mg, quant.) as an amorphous solid.

Step 3: Preparation of Compound 11-5

Amine HCl salt 11-3 (201 mg, 0.614 mmol) and phenoxy compound 11-4 (176mg; 0.608 mmol) were suspended in CHCl₃ (6.0 mL) and triethylamine(0.200 mL), and the suspension was refluxed for 3 h. The resultingmixture was cooled to room temperature. After diluting with ethylacetate, the organic layer was washed with aqueous NH₄Cl, saturatedaqueous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was suspended with ethanol andcollected to give urea 11-5 (235 mg; 84%) as a solid.

Step 4: Preparation of Compound 11-6

Urea 11-5 (200 mg) was dissolved in methanol (3.0 mL) and THF (3.0 mL)and the solution was treated with 2N NaOH aqueous (3.0 mL) at 60° for1.5 h. The resulting mixture was poured into water and extracted withethyl acetate, and washed with brine. The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was suspended with ethylacetate and hexane, and collected to give thiol 11-6 (155 mg; 85%) as awhite solid.

Step 5: Preparation of Compound 1100

To the solution of thiol 11-6 (79.5 mg) in anhydrous methanol (3.0mL)was added sodium methoxide (31.1 mg) and methyl iodide (0.036 mL). Afterbeing stirred for 12 h at room temperature, the resulting mixture wasdiluted with ethyl acetate and washed with water and brine. The organiclayer was dried (Na₂SO₄) and concentrated in vacuo. The residue wastriturated with IPE to give methylthio compound 1100 (72.6 mg; 88%) as awhite solid.

EXAMPLE 122,3-Dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide1200

To a solution of2,3-dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide(1100, 55.4 mg, 0.129 mmol) in methanol (3.0 mL), THF (2.0 mL) and H₂O(1.0 mL) was added sodium meta periodade (34.6 mg, 0.161 mmol). Afterbeing stirred for 35 h at room temperature, the resulting mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried (Na₂SO₄), and concentrated invacuo. The residue was triturated with ethyl acetate and isopropyl etherto give2,3-dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide45.4 mg; 79%) as an amorphous solid, 1200.

1H-NMR (CDCl3) δ ppm: 1.90-2.10 (4H, m), 2.30-2.50 (1H, m), 2.50-2.70(0.5 H, m), 2.48 (1.5H, s), 2.55 (1.5H, s), 2.73-2.82 (0.5H, m),3.05-3.30 (2H, m), 4.00-4.30 (2H+0.5H, m), 4.39-4.47 (0.5H, m),6.55-6.67 (0.5H, brs), 6.67-6.80 (0.5H, brs), 7.20-7.60 (13H, m). FABMS:446 (M+H)

EXAMPLE 134-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride, 1300

Step 1. Preparation of4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine(13-1)

A solution of 3-chloro-2-pyridylacetonitrile [prepared by the methoddescribed in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) was slowlyadded to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and the mixturewas stirred at room temperature for 1 h. A solution ofN,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO(19 mL) was added, and the resulting mixture was stirred at 75° C. for 4h. After cooling, water (100 mL) was added, and the mixture wasextracted with ethyl acetate. The organic extract was washed with brine,dried (Na₂SO4), and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/2) to give4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine1(1.91 g, 60%) as an orange oil.

Step 2. Preparation of4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (13-2)

A mixture of4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine (1.91g, 5.59 mmol) and lithium tri-tert-butoxyaluminohydride (1 M solution inTHF, 22 mL) in 1,4-dioxane (28 mL) was stirred at 125° C. overnight in asealed tube. After cooling, 1 N aqueous NaOH solution (50 mL) and ethylacetate were added to the mixture, and the mixture was filtered throughCelite. The organic layer was separated and washed with brine, dried(NaSO4), and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=7/3→chloroform/methanol=9/1) to give4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (2)(0.80 g, 46%) as an orange solid.

Step 3. Preparation of4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-Piperidine](13-3)

To a suspension of4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (0.80 g,2.59 mmol) in ethyl acetate (13 mL) were added Et₃N (1.08 mL, 7.77 mmol)and methylsulfonyl chloride (0.24 mL, 3.1 mmol) at 0° C., and themixture was stirred at the same temperature for 1.5 h. The mixture wasdiluted with ethyl acetate, washed with brine and dried (NaSO4). Thesolvent was evaporated in vacuo, and the residue was purified by silicagel column chromatography (chloroform/methanol=99/1) to give4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](476 mg, 47%).

Step 4. Preparation of4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (13-4)

A mixture of4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](476 mg, 1.23 mmol), cyclohexene (3 mL) and 10% Pd/C (500 mg) in ethanol(12 mL) and THF (12 mL) was refluxed for 5 h. The catalyst was removedby filtration, and the filtrate was concentrated under reduced pressure.Purification of the residue by column chromatography on alumina(chloroform/methanol=9/1) gave4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (102 mg, 31%).

Step 5. Preparation of4-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride, 1300

A mixture of 4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (100mg, 0.37 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (108 mg, 0.37mmol) and Et3N (0.26 mL, 1.87 mmol) in CHCl3 (1.9 mL) was refluxed for1.5 h. After cooling, the mixture was diluted with EtOAc, washed withaqueous saturated NaHCO3 and brine, dried over MgSO4, and concentratedunder reduced pressure. The residue was dissolved in chloroform, and 4 NHCl/ethyl acetate (0.38 mL) was added. The solvent was evaporated, andthe residue was crystallized from methanol, chloroform and diisopropylether to give4-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride (143 mg, 76%) as a brown powder. m.p.: 138-145° C.

1H-NMR (CDCl3) was consistent with the proposed title structure. FABMS:465 (M+H)

EXAMPLE 147-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,(1400)

Step 1. Preparation of4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine(14-1)

A solution of 2-chloro-3-pyridylacetonitrile [prepared by the method ofBremner, et al, Synthesis, 1992, 6, 528-530] (2.14 g, 14.0 mmol) in DMSO(28 mL) was slowly added to NaH (60% in oil, 1.51 g, 37.8 mmol), and themixture was stirred at room temperature for 1 h. A solution ofN,N-bis(2-chloroethyl)-p-methoxybenzylamine (3.67 g, 14.0 mmol) in DMSO(28 mL) was added, and the resulting mixture was stirred at 75° C. for 4h. After cooling, the mixture was partitioned between water and ethylacetate, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with 1 N aqueous NaOH solution andbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate 9/1→1/1) to give4-(2-chloro-3-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1(1.62 g, 34%) as a brown solid.

Step 2. Preparation of7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (14-2)

A mixture of4-(2-chloro-3-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine (1.62g, 4.74 mmol) and lithium tri-tert-butoxyaluminohydride (1 M solution inTHF, 19 mL) in 1,4-dioxane (24 mL) was stirred at 130° C. overnight in asealed tube. After cooling, 1 N NaOH (50 mL) and EtOAc were added to themixture, and the mixture was filtered through Celite. The organic layerwas separated and washed with brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate 4/1→chloroform/methanol 9/1) togive 7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (2)(0.96 g, 66%) as a brown solid.

Step 3. Preparation of7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspirorindoline-3,4′-piperidine](14-3)

To a suspension of7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (0.96 g,3.10 mmol) in EtOAc (16 mL) were added Et₃N (1.30 mL, 9.30 mmol) andmethylsulfonyl chloride (0.36 mL, 4.65 mmol) at 0° C., and the mixturewas stirred at the same temperature for 2 h. The mixture was dilutedwith EtOAc, washed with brine and dried (Na₂SO₄). The solution waspassed through a pad of silica gel and the pad was washed with ethylacetate. The filtrate and washing were combined, and the solvent wasevaporated to give7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](0.99 g, 82%) as a brown amorphous solid.

Step 4. Preparation of7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (14-4)

A mixture of7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](0.82 g, 2.12 mmol), cyclohexene (5 mL) and 10% Pd/C (0.82 g) in EtOH(20 mL) and THF (20 mL) was refluxed for 2 h. The catalyst was removedby filtration, and the filtrate was concentrated under reduced pressure.The residue was reprecipitated from MeOH, EtOAc and IPE to give7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (0.47 g, 83%) as abrown powder.

Step 5. Preparation of7-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,1400

A mixture of 7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (134mg, 0.50 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (116 mg, 0.45mmol) and Et3N (0.35 mL, 2.5 mmol) in CHCl3 (2.5 mL) was stirred at 90°C. in a sealed tube for 1.5 h. After cooling, the mixture was dilutedwith EtOAc, washed with NaHCO3 and brine, dried (Na₂SO₄), andconcentrated under reduced pressure. Purification of the residue bycolumn chromatography on silica gel (hexane/ethylacetate=7/3→chloroform/methanol=9/1) gave7-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide(181 mg, 78%) as a white powder. m.p.: 214-215° C.

1H-NMR (CDCl3) was consistent with the proposed title structure. FABMS:465 (M+H)

Compound #1401 and #1402 were prepared from7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] and phenylN-(4-benzoylphenyl)carbamate or phenylN-(3-phenyl-5-isoxazolyl)carbamate, respectively, according to theprocedure described in Example 14.

#1401

7-aza-N-(4-benzoylphenyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

1H-NMR (DMSO-d6) δ ppm: 1.69-1.90 (4H, m), 3.02-3.12 (2H, m), 3.29 (3H,s), 3.97 (2H, s), 4.05-4.20 (2H, m), 7.00 (1H, dd, J=7.5, 5.0 Hz),7.50-7.80 (10H, m), 8.12 (1H, dd, J=5.0, 1.4 Hz), 9.0 (1H, brs).

#1402

7-aza-N-(3-phenyl-5-isoxazolyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 211-212° C.

EXAMPLE 15 1-Methylsufonyl-N-(4-ethoxycarbonylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide 1500

To a stirred solution of1-methylsulfonyl-spiro[indoline-3,4′-piperidine] (2.66 g, 10 mmol) indichloromethane (50 mL), was added ethyl 4-isocyanatobenzoate (1.91 g,10 mmol) at room temperature. The resulting solution was stirred forfour hours during which time precipitation occurred. The mixture wasevaporated to remove dichloromethane, and then was suspended in methanol(20 mL), filtration followed by washing with cold methanol gave 1500 asa white solid (4.56 g, 100%)

NMR (CDCl3, 300 MHz): δ ppm 8.00 (d, J=8.8 Hz, 2H); 7.46 (d, J=8.8 Hz,2H); 7.43-7.06 (m, 4H); 6.62 (s, 1H), 4.36 (q, J=7 Hz, 2H), 4.14 (br. D,J=13 Hz, 2H); 3.90 (s, 2H), 3.09 (dt, J=1, 13 Hz, 2H); 2.94 (s, 3H),2.00 (dt, J=4, 13 Hz, 2H), 1.82 (br. d, J=13Hz, 2H), 1,38 (t, J=7 Hz,3H). ESI-MS: 458 (M+1)

The following compounds were similarly prepared from1-methylsulfonyl-spiro[indoline-3,4′-piperidine] and the appropriateisocyanates.

#1501

1-methylsufonyl-N-(4-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1502

1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 428 (M+1);

#1503

1-methylsufonyl-N-(4-methylthiophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1504

1-methylsuonyl-N-(3,4-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 454 (M+1);

#1505

1-methylsufonyl-N-(4-phenylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 462 (M+1);

EXAMPLE 161-Methylsufonyl-N-(4-(2-hydroxyethyl)phenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide1600

To a stirred solution of1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide(400 mg) in ethanol/dichloromethane (5/5 mL) at 0° C., was added sodiumborohydride (100 mg). The mixture was stirred for 1 hour, then 3 N HCl(0.2 mL) was added to destroy the excess hydride. The mixture was thenconcentrated and partitioned between water and dichloromethane. Theorganic layer was dried over MgSO4 and evaporated to give the titlecompound, 1600 as white powder (386 mg). ESI-MS: 430 (M+1)

EXAMPLE 171-Sulfamoyl-N-(3,4-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide1700

This compound was prepared from1-sulfamoylspiro[indoline-3,4′-piperidine] (L. Guo, A. Patchett, L.Yang, U.S. Pat. No. 5,783,582, Jul. 21, 1998.) and 3,4-dichlorophenylisocyanate by the same procedures described in Example 15

NMR (DMSO-d6, 400 MHz): δ ppm: 8.84 (s, 1H), 7.87 (s, 1H), 7.47 (s, 2H),7.31-7.25 (m, 4H), 7.18 (t, J=7.6 Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 4.13(d, J=13.6 Hz, 2H), 3.81 (s, 2H), 3.02-2.94 (m, 2H), 1.79-1.74 (m, 2H),1.65 (d,J=13.2 Hz, 2H). ESI-MS: 455 (M+1)

Employing substantially the same procedure as described in Example 15,the following compounds were prepared from1-sulfamoyl-spiro[indoline-3,4′-piperidine] and the appropriateisocyanate.

#1701

1-Sulfamoyl-N-(4-ethoxycarbonylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 459 (M+1);

#1702

1-Sulfamoyl-N-(4-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1);

#1703

1-Sulfamoyl-N-(3,4-dimethylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 415 (M+1);

#1704

1-Sulfamoyl-N-(2,4-dimethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 447 (M+1);

#1705

1-Sulfamoyl-N-(2,6-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 455 (M+1);

#1706

1-Sulfamoyl-N-(3-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1)

#1707

1-Sulfamoyl-N-(4-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

#1708

1-Sulfamoyl-N-(2-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1);

#1709

1-Sulfamoyl-N-(3-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

#1710

1-Sulfamoyl-N-(2-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

#1711

1-Sulfamoyl-N-(4-ethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1712

1-Sulfamoyl-N-(2-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1713

1-Sulfamoyl-N-(4-phenyloxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 479 (M+1);

#1714

1-Sulfamoyl-N-(4-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 417 (M+1);

#1715

1-Sulfamoyl-N-(3-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1716

1-Sulfamoyl-N-(3-ethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

#1717

1-Sulfamoyl-N-(4-isopropylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 429 (M+1);

#1718

1-Sulfamoyl-N-(2-ethylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 415 (M+1);

#1719

1-Sulfamoyl-N-(4-methylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

#1720

1-Sulfamoyl-N-(3-methylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

#1721

1-Sulfamoyl-N-phenyl-spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

#1722

1-Sulfamoyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamideESI-MS: 429 (M+1);

EXAMPLE 18trans-N-(5-acetyl-2-pyrimidinyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamide(#1800)

Pyridine (0.121 mL, 1.50 mmol) andtrans-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] (92.8 mg, 0.330 mmol) wereadded to a solution of 2-chloro-1,3-dimethylimidazolium chloride (152mg, 0.90 mmol) in CHCl₃ (0.800 mL) and THF (0.800 mL). After stirringfor 5 min at room temperature, 2-amimo-5-acetylpyrimidine was added tothe mixture. The resulting mixture was stirred at room temperature for2.5 h. The mixture was diluted with EtOAc, washed with 5% KHSO₄, sat.NaHCO₃ and brine, dried (MgSO₄). After removal of the solvent, theresidue was purified by column chromatography on silica gel(CHCl₃/MeOH=100/0→99/1) to give an oil, which was triturated withEtOAc-hexane to give 1800 (93.8 mg, 56%) as a white powder. m.p.:100-105° C.

Compounds #1801-1803 were prepared from 2-amino-5-acetylpyrazine inanalogy to the procedure of Example 10.

#1801trans-N-(5-acetyl-2-pyrazinyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 220.8-221.2° C.

The following compounds #1802-#1803 were prepared from6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] and the appropriate amines inanalogy to the procedure of Example 10.

#1802

trans-N-(5-acetyl-2-pyrimidinyl)-6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 196-198° C.

#1803

trans-N-(5-acetyl-2-pyrazinyl)-6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 228.1-228.3° C.

The following compounds #1804-#1805 were prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] and the appropriate amines inanalogy to the procedure of Example 10.

#1804

trans-N-(5-acetyl-2-pyrimidinyl)-5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 210.5-211.7° C.

#1805

trans-N-(5-acetyl-2-pyrazinyl)-5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 209.3-209.6° C.

EXAMPLE 19 Determination of IC₅₀

LMtk-cells expressing human Y5 receptors were washed with 50 mM HEPESbuffer (pH 7.4) containing 20% sucrose, homogenized and centrifuged at1,000×g for 15 min. The supernatant was centrifuged at 100,000×g for 45min. The pellets were resuspended in 5 mM HEPES buffer (pH 7.4) andcentrifuged again. The membrane fraction was resuspended by ahomogenizer in the same buffer and used for this study.

Binding of [¹²⁵I]PYY to the membrane was performed in 0.2 ml of 25 mMTris buffer (pH 7.4) containing 10 mM MgCl₂, 1 mM PMSF, 0.1% bacitracinand 0.5% BSA. The membranes (100-300 μg/ml) were incubated at 25° C. for120 min with [¹²⁵I]PYY (25 pM). Bound and free peptides were separatedby filtration using a GF/C glass filter (Whatman, England) presoakedwith 0.3% polyethylenimine. The remaining radioactivity on the filterwas quantitated using a Cobra™ (Packard, Japan). Specific binding of[¹²⁵I]PYY was defined as the difference between total binding andnonspecific binding in the presence of 1 μM PYY.

Employing the procedure described in Example 18, a representative numberof the compounds of this invention were found to have IC50 values lessthan 1 mM.

Using procedures similar to those described in Example 18, in whichmembranes expressing other NPY subtypes are used in place of the Y5membranes, many of the compounds of this invention have greatselectivity for the Y5 receptor over the NPY Y1, Y2 and Y4 receptors.For example, many of the compounds of this invention have IC50>1000 nMon Y1, Y2 and Y4 receptors.

EXAMPLE 20 Effect of Compound 100 on Bovine Pancreatic Polypeptide(bPP)-induced Food Intake in Spraque-Dawley Rats

Materials and Methods

Male Sprague-Dawley rats aged 7 weeks (Charles River, Japan) weremaintained under the controlled temperature (23±3° C.), humidity(55±15%) and light-dark cycle (7:00-19:00 light on). Rats were housedindividually with ad libitum access food (CE-2, Clea Japan) and tapwater.

Rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.,Dainabot, Japan). A permanent stainless steel guide cannula forintracerebroventricular (ICV) injection (21 gauge, 10 mm long) wasstereotaxically implanted into the right lateral ventricle. Thestereotaxic coordinates used were as follows: 0.9 mm posterior and 1.2mm lateral to the bregma and 1.5 mm ventral to the brain surface.

Animals were allowed at least 6-day recovery postoperatively before thestart of feeding experiment. The day before the experiment, they werehandled and underwent mock injection, and nocturnal food intake wasmeasured. Rats which ate more than 15 g during the night before theexperiment were used for the following experiment.

Test compounds were suspended in 0.5% methylcellulose and orallyadministered by gavage. Administration of test compounds usually beganat 10:00. Dosing volume was 5 ml/kg. One hour after the drugadministration, bovine pancreatic polypeptide (PP, 5 g/10 l/1 min) wasICV injected through a stainless steel injector (26 gauge) attached to a50 l Hamilton microsyringe by polyethylene tubing. The injector extended2 mm beyond the end of the guide cannula. Bovine PP was dissolved in 10mM PBS containing 0.05% BSA. Two hour post-injection food intake wasmeasured for each rat.

Results

Compound 100 was orally administered 1 hour prior to the ICV-injectionof bPP in satiated male Sprague-Dawley rats. Compound 100 (1, 3, 10 and30 mg/kg) suppressed bPP-induced food intake in a dose-dependent manner,and the minimum effective dose is estimated to be 3 mg/kg. Furthermore,this compound at 100 mg/kg, p.o. did not cause any abnormal behavior inrats and mice during 24 hour after dosing. Thus, Compound 100 has apotent in vivo Y5 antagonistic activity without causing any abnormalbehavior.

EXAMPLE 21A

Tablets containing 1-25 mg of compound Amount mg Compound of formula I1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 Modified foodcorn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 Magnesium stearate 0.50.5 0.5

EXAMPLE 21B

Tablets containing 26-100 mg of compound Amount mg Compound of formula(I) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modifiedfood corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Magnesiumstearate 0.5 0.5 0.5

What is claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein; V and W areindependently selected from CH and N, provided that V and W cannotsimultaneously be CH and that V and W cannot simultaneously be N; R¹ isH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, or C; R² is S(O)n R⁶, COR⁶ or CHO,wherein n is 0, 1 or 2; and R⁶ is N(R³)₂ or C₁₋₃ alkyl; R³ isindependently H or C₁₋₃ alkyl; Ar is aryl or heteroaryl; R⁴ and R⁵ areindependently selected from: (1) hydrogen, (2) aryl, eitherunsubstituted or substituted with (a) halo (b) C₁₋₃ alkoxy, (c)-N(C₁₋₃alkyl)2, (d) C₂₋₄ alkanoyl, or (e) aryl; (3) nitro, (4) C₁₋₅ alkyl, (5)C₁₋₅ alkoxy, (6) hydroxy-C₁₋alkyl, (7) carboxy, (8) halo, (9) C₁₋₅alkythio, (10) C₁₋₅ ethoxycarbonyl, (11) pyridylcarbonyl, (12) benzoyl,(13) phenyl-C₁₋₃ alkoxy, (14) pyridyl, either unsubstituted orsubstituted with C₁₋₃ alkyl or C₁₋₃ alkoxy, (15) C3-6 cycloalkyl, (16)oxazolyl, (17) thiazolyl, (18) triazolyl or (19) phenoxy.
 2. Thecompound of claim 1 wherein Ar is phenyl, of structural formula I(a)

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2 wherein R² is —SO₂(C₁₋₃ alkyl) or SO₂NH₂.
 4. The compound of claim 3wherein R⁴ and R⁵ are independently selected from: phenyl, pyridyl,benzoyl, halophenyl, phenoxy, C₁₋₅ alkylpyridyl, benzhydryl, phenyl-C₁₋₃alkoxy, NO₂, C₂₋₄ alkanoyl, halo, C₁₋₅ alkoxy, C₁₋₃ alkoxycarbonyl, C₁₋₅alkylthio, triazolyl, carboxy, hydrogen, C₁₋₅ alkyl, pyridylcarboxy, andC₁₋₃ alkoxyphenyl.
 5. The compound of claim 4 or a pharmaceuticallyacceptable salt thereof selected from those depicted in the followingTable: R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂NH₂

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂C₂H₅

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂C₂H₅

—SO₂CH(CH₃)₂

—SO₂CH(CH₃)₂


6. The compound of claim 5 wherein Ar is a 5- or 6-membered heteroarylhaving, besides carbon atoms, 1 to 3 hetero atoms selected from N, O orS as atoms constituting the ring, or benzo- or pyrido- fused versionsthereof or a pharmaceutically acceptable salt thereof.
 7. The compoundof claim 6 wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂N(C₁₋₃ alkyl)2.
 8. Thecompound of claim 7 wherein the heteroaryl group, Ar, is selected from:thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, benzothiazolyl, oxazolyl,pyridothiazolyl, benzoxazolyl, quinolyl, pyrazinyl, thienyl, isoxazolyl,pyrimidinyl, benzimidazolyl, oxadiazolyl, and imidazolyl.
 9. Thecompound of claim 8, or a pharmaceutically acceptable salt thereof,selected from those depicted in the following Table: R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂N(CH₃)₂

—SO₂NH₂

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅


10. The compound of claim 1 wherein R² is —COR⁶ of structural formulaI(b):

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim10 or a pharmaceutically acceptable salt thereof selected from thosedepicted in the following Table: R⁶

—CH₃

—CH₃

—CH₃


12. The compound of claim 1 of structural formula I, wherein one of V orW is nitrogen and the other is —CH═.
 13. The compound of claim 12wherein R¹ and R³ are both hydrogen.
 14. The compound of claim 13wherein R² is —SO₂CH₃ or —SO₂NH₂.
 15. The compound of claim 14 selectedfrom the compounds depicted in the following TABLE V W

—N— —CH═

—CH═ —N—

—CH— —N—

—CH— —N—


16. A pharmaceutical composition which comprises a pharmaceuticallyacceptable carrier and an effective amount of a compound of claim 1.